rs886037841

Variant names:

• chr3-171188803-G-A
• rs886037841
• NM_015028.4:c.538C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015028.4(TNIK):​c.538C>T​(p.Arg180*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNIK NM_015028.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.95
• Publications: 1 publications found

Genes affected

TNIK (HGNC:30765): (TRAF2 and NCK interacting kinase) Wnt signaling plays important roles in carcinogenesis and embryonic development. The protein encoded by this gene is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. Mutations in this gene are associated with an autosomal recessive form of cognitive disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

TNIK Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 54

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-171188803-G-A is Pathogenic according to our data. Variant chr3-171188803-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 243022.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015028.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	NM_015028.4	MANE Select	c.538C>T	p.Arg180*	stop_gained	Exon 7 of 33	NP_055843.1
	TNIK	NM_001161560.3		c.538C>T	p.Arg180*	stop_gained	Exon 7 of 32	NP_001155032.1
	TNIK	NM_001161561.3		c.538C>T	p.Arg180*	stop_gained	Exon 7 of 32	NP_001155033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	ENST00000436636.7	TSL:1 MANE Select	c.538C>T	p.Arg180*	stop_gained	Exon 7 of 33	ENSP00000399511.2
	TNIK	ENST00000284483.12	TSL:1	c.538C>T	p.Arg180*	stop_gained	Exon 7 of 32	ENSP00000284483.8
	TNIK	ENST00000357327.9	TSL:1	c.538C>T	p.Arg180*	stop_gained	Exon 7 of 32	ENSP00000349880.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal recessive 54 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.9
Vest4		0.83
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037841; hg19: chr3-170906592; COSMIC: COSV52681744;